The impact of genomics on the discovery and development of drugs at SmithKline Beecham - Dr Christine Debouck - SmithKline Beech

Case Study: The impact of genomics on the discovery and development of drugs in a large pharmaceutical company. Dr Christine Debouck VP & Director, Biotechnology and Genetics Worldwide

Case Study: The impact of genomics on the discovery and development of drugs in a large pharmaceutical company.

Dr Christine Debouck
VP & Director, Biotechnology and Genetics Worldwide
SmithKline Beecham

I am Christine Debouck. My title indicates I work in a large company. I didn'st know at the time if we were still going to be SmithKline Beecham or Glaxo SmithKline; as of today we are still SmithKline Beecham. We have had a difficult task to work with our future colleagues from Glaxo Wellcome to plan GSK, as it is going to be called, but at the same time behave as competitors. So all what you are going to hear today is exclusively work done in my current company SmithKline Beecham.

One of the things I want to say in terms of some of the key attributes of doing this type of research in Big Pharma is emphasize some of the fundamental positive aspects of Big Pharma. We are not just, as I said yesterday, large dinosaurs with very small heads and no ideas and no brains; this is a business that has been in business for a very long time building a tremendous amount of experience, of expertise but scientific excellence, creativity, innovation is definitely not something that is absent from our daily activities and I hope that through my presentation as well the subsequent presentations you will be convinced of that in case you had no knowledge of that or lost faith in the fact that there was still good science and good creativity applied to drug discovery.

Something else is, something I could designate as global properties. Not only a lot of pharma companies are global in the literal sense of the term, that is with presence in various parts of the globe, that gives a tremendous advantage and a tremendous richness in the way we operate to have the capability of working trans-nationally. In my own organization, it is SmithKline Beecham, in my own division every single one of the seven departments is organized twice nationally with one department director and folks working in the US, folks working in the UK, totally together, totally integrated and it brings a tremendous value and the first thing that employees down to technical staff said when the merger with Glaxo Wellcome was announced is Are we going to still work trans-nationally?, so it is even valued by the employees.

Something that is also a global aspect is that we cover all of the disciplines and you can just walk to the next building and talk to a lawyer, you can be exposed to people who do drug development. It is very often described as a mindless process, a very good process but totally mindless and non-creative and actually do a tremendous scientific excellent thing, creativity going on there as well.

The last point is there is a lot of structure when you look at a Big Pharma company. There is an executive, VP and directors and all these layers that you could say could actually be an impediment and a flat organization can move more quickly. Actually, you know, there is value in both types of organizations but a structured organization with a people in charge of people with some kind of hierarchy provides tremendous opportunities for leadership, leading by example and mentorship and that is something that I used to be one of the young scientists working at the bench and I still consider myself young, but now I feel that I have a responsibility to actually mentor people and

bring them along in terms of teaching them professional ethics and good professional integrity and along with that goes obviously internal education.

One thing I wanted to make as a comment based on something that was said yesterday by Bill Haseltine that the future of the drug industry is going to no longer reside or less and less reside in small molecules. I really do not agree with that statement however I think that I agree with the statement that protein therapeutics have a major role to play and can be developed very rapidly when they are discovered and analyzed properly. This is something that is an activity going on at SmithKline Beecham. We have actually many times been approached by small biotech companies because we have the know-how not only to discover protein therapeutics but also to develop them and to manufacture them but I'sm not going to talk about protein therapeutics today.

What I would like to talk about is framing the context of what genomics, and I would focus exclusively on genomics today not on genetics, where genomics can have an impact and obviously something that everybody is aware of is the selection of targets right up front. Genomics is really providing the opportunity through the discovery of new genes to identify new targets, but also what I want to stress with this particular slide is that this is an old process. The process of drug discovery and drug development is an old process but new technologies are really facilitating that process but fundamentally it is like I said earlier today, it is a new tool in the box. A new tool in the box is genomics, a new tool in the box is going to be the capability of creating very large numbers of compounds very rapidly through combinatorial chemistry. You don'st see the compounds very well and that is typical of Big Pharma, this structure is unproprietary, I don'st want you to write them down, screening also tremendous revolution in miniaturization, setting up high throughput screening to be able to screen compounds very rapidly both in the wet's sense of the term, through an assay but also screening through virtual screening by obtaining 3-dimensional structures of the targets and a screening in the computer for compounds that may fit. So that is why we call them molecular dentistry, things that fit in the cavity of the active side. And obviously as you find these you will need to demonstrate the biology, demonstrate the efficacy in animals, the lack of toxicity in animals before you progress on to humans. And genomics not only will have an impact in identifying new targets but also in facilitating the various aspects of compound selection, for example through toxicogenomics, trying to identify through the use of proteomics or micro arrays possible adverse toxic effects of a given compound and also obviously in the clinic there is not just the pharmacogenetics but also the pharmacogenomics, but I will not discuss that today.

So clearly we have a new tool in the box and that tool is genomics, high throughput sequencing, a variety of other technologies, micro arrays and so on and so forth and we went from knowing relatively little about genes, having relatively genes on hand to having basically all of the genes. We can argue that a hundred thousand is it forty thousand, that's not the point of the slide, the point of the slide was we had few genes on hand, the number of targets that .had targets now for current drugs is 483, whatever the number is, and obviously there is a lot more to discover, not just in terms of genes but genes with value added. So that is a target, a gene by itself is not going to be a target unless you know what role it plays in normal physiology and in disease.

What I want to do today is I want to actually crank up the notch of scientific value to the presentation. We have heard a lot of more general presentations and you should not be

intimidated because it is not going to be overly scientific. I have left the bench in 1992, so you are not going to get tremendous details but I want to show you clear examples of how we have actually used genomics to identify new targets and progress them and the first one goes back to the early days of high throughput sequencing that we were doing in collaboration with human genome science and I want to walk you through the discovery of a target for us to process and that gene is called Cat* and very rapidly we were able to go from an idea through sequencing and identification of this target and the idea was actually before we made the deal with Human Genome science, we said it would be great to identify new genes for us to process and I will show that the culprit cell in the process of bone degradation is the osteoclast and we thought that if we would collect all the genes that are turned on in an osteoclast, because all the cells of your body, wherever they are have the same compliment of genetic information, all the same chromosomes but the genes are not turned on in the brain are different from the ones turned on in the liver, in the muscle or in the osteoclast. So making CDNA is just a technical term to say you are going to grab all the genes that are turned on in a particular cell. So we did this, we did sequencing and then in a span of a few weeks we actually identified a new gene that turns out to be a new target for osteoporosis and I will walk you through this.

What was very important is we didn'st start from nowhere. I showed the wave this morning that was picked by the surfer. We chose very selectively what we wanted to sequence. You can sequence the whole genome but at the time in the early nineties we were not sequencing the whole genome, we would sequence selected sets of express genes and we worked with the biologist who knew the best, the problem of osteoporosis and it is very well known, it is a very simple scientific fact, biological fact that osteoporosis results from an imbalance of bone reabsorbtion, that is done by the osteoclast, easy to remember; an iconoclast in the past was somebody breaking images, an osteoclast is actually breaking bone and formation, that is done by the osteoblast and a blast may sound like something is broken but actually it is construction of something using Greek, very high incidence, everybody knows about this, and what is important is if you zoom in on what is the process of bone reabsorbtion, the bone is made of a mineral matrix and a protein matrix. The mineral matrix has to be dissolved by low PH. If you an accumulation of calcium carbonates in your teapot you are going to pour vinegar, vinegar is acid. So again, very simple principle and the protein is actually degraded by proteases, these proteases are enzymes that are going to digest proteins and we knew that inhibitors of a sub class of proteases is called a cystine proteases would be capable of blocking bone reabsorbtion. So we said one of the things we should look for are novel proteases that are members of the cystine proteases family.

So what we did, this is actually a cartoon that shows an osteoclast, this is actually a very large cell, it is the result of fusion between many cells and it is sitting on the bone and what it does is it forms this very tight seal to sit on the bone and then it is secreting acid, so it is making its own vinegar, and then it is secreting here a proteases or maybe more than one proteases to digest the protein and it is making this little pit that is actually called the resorption pit.

These cells, if you want to isolate the genes that are turned on in osteoclast, you need to get osteoclast. Osteoclasts are very difficult to get, they don'st grow in shared culture, you can grow a lot of cells into shared culture, osteoclast don'st grow into shared culture. What we were able to do was, most bone tumors are actually not the derived from these

cells but there are some very rare bone tumors that are derived from osteoclast. So again a specialized knowledge but keeping things very simple.

The problem with these tumors is they are a mix of osteoclast and other cells and the knowledge of this tight seal being formed; we had information that the specific protein makes this very tight seal and we had made an antibody against it so we could go and grab the cells specifically using that antibody. So again very simple principles but very expert knowledge.

The osteoclasts were purified, we isolated the genes that are turned on in that particular cell and what we did is we did sequencing, I'sm not going to get into the technical terms but you can see this is the sum of all the genes that were sequenced after, you know, a couple of weeks, not even that a week or maybe two maximum, and among over 5000 genes that were sequenced there was a nice bunk here of 4% of the hits that were found all came from one gene. It meant that that gene was turned on at high levels, so we had many copies of that particular gene.

It looked like papain, papain is made by papaya the fruit, it is a proteases, actually people take it to help digestion, digestion needs to degrade proteins, meat especially; it is also a meat tenderizer. We send Well, could it be a protein involved in the digestion of collagen in the bone, and it looked pretty reasonable. We had something that was a hit and was very abundant, but you need to go and demonstrate this very carefully, not just take it for granted that you have got it. So what we did is we used a couple of techniques that can go and very specifically look at what gene is turned in the osteoclast using some specific tools, one technique is called in situ to hybridization, I will show you a picture that is much more than these words, another one is through making an antibody that is very specific for Cat* and look in a cell. So the in situ to hybridization looked at the gene as it is turned on as R&A and the antibody will look at the protein.

And the first picture I have is actually the in situ to hybridization. What you do here is you use a probe that is very specific for Cat* and you detect it and these big cells are all osteoclast, this is actually a piece of bone here and you have the osteoclast sitting around the bone. What was much more telling and picture of something going on to validate this part of the target was using the antibody, the antibody that is specific for Cat* when it binds to it will give this red colour and what you see is, this is an osteoclast and it is in red but you have more density on this side of the cell and actually if you stain it with other red agents you will find that this particular structure here is a piece of bone. So what you add is the osteoclast, like in the cartoon I had, sitting on the bone with the majority of it Cat* enzyme sitting on the side of the cell that was on the bone. So you could see bone reabsorbtion in action and this particular picture is actually worth a thousand words in terms of this is a validated target. The ultimate demonstration is to identify an inhibitor for this particular enzyme and show that it works to prevent osteoporosis but we felt that this demonstration was actually very, very strong and it would warrant putting chemists and a whole team of enzymologists and biologists together to pursue this particular target.

Just to show you that we went on to produce the protein and work on systems, purify the protein, characterize it through detail enzymology and it is indeed collagenous. Collagen is the major component of bone and we went on to do more work..I'sm skipping months and months of work here. This is actually the 3-dimensional crystal structure of patain,

that is all we had at the beginning, we didn'st have buckets of Cat* yet and Lupatsin is a known inhibitor of cystine proteases, so we had solved a structure and it bound here, then we had developed some inhibitors of CatapsincK and we found that the bound on the other side of the active side and we said well what if we put those two things together and create a new compound, would we increase the affinity of the compound for the enzyme? and that is exactly what happened. This compound was made, this is an early compound and you can see this is for those who know what these narrow numbers mean. This is a very potent compound. We have much more potent then that now and this compound spanned a whole active site.

Where we are with this particular project is we had the pre-clinical stage, we had some problems. protease is actually very difficult targets. This is one of the initial targets, we moved very, very quickly but there are things that in the drug discovery process are still very difficult to tackle. proteases is, remember HIV proteases, they took a long time to get something that went all the way to the market. You need to get oral availability, stability of the compound, something that we rate as difficult early on is that the inhibitors that we had developed, sorry about that, the inhibitor that we had developed early on were not working against the rat enzymes so we could not demonstrate efficacy in the animal models. This is something that we do know right up front is we clone immediately the corner part from the rat or the ferrets or the guinea pig or whatever species is going to be used for the animal model. So as I said we have some compounds that look very good, now I have passed all the hurdles and have entered already pre-clinical developments and hopefully will make it all the way to phase 1 in men.

Another type of targets, I can give you the story from many different targets. One story that I would like to tell you is the one of gene family so that you can actually develop a process for one, like we did with Cat* but then apply it systematically in exactly the same manner for all the members of that family and I personally worked on proteases and each one is its own beast. I actually am one of the first discoverers of HIV protease, then I worked on Herpes protease, I worked on protease involved in apoptosis, I have worked on this one, most of these with my own hands and every one you had to discover how it works, what does it do. You would gain tremendous knowledge and .but you could not apply it systematically to other members of the family except if they were very close cousins. So we have very close cousins of Cat* and we are working on them for other diseases. But the so called Seven trans membrane receptors, also called G Protein couple receptors, I like to call them Seven trans membrane receptors because most people relate to that a little bit better, the protein goes seven times through the outer membrane of the cell and we have through a variety of approaches whether it was HTS database, public database, our own gene cloning activities, we have discovered in excess of two hundred slides. This two hundred receptors, this slide becomes obsolete on a weekly basis however the number is dwindling down a little bit now that we have access to a lot of human genome information.

What is nice about this is that they fall in some sub families but they all do the same thing. They will interact with light, that's the way you see, actually it is also the way you taste and smell and you can see that they have, you know, some different structures on the outside, the way they interact with the outside environment of the cell but then they will communicate inside of the cell through these G Proteins. So that is why they are also called G Protein Couple Receptors.

So to date a lot of these receptors have been well characterized and there are a lot of drugs out there that are antagonist or agonist of receptors that belong to this family. For us and other companies Tagonet, Pepsid were antagonist of a histamine receptor in the stomach and made a lot of money for the treatment of ulcers, so Ceratone receptors are other members, so there are a lot of compounds already marketed, very successful drugs, that are targeting members of this particular family. So that means there is a tremendous not only experience with these types of gene targets but also a tremendous wealth of compounds in all the banks from major pharma companies but at the same time I don'st think it is just that the compound banks are biased towards these receptors because we have worked on them so successfully, I think a receptor located on the outside of the cell is a very attractive target compared to something located in the nucleus.

So as I said we have discovered in excess of 200 and we have put a very extensive process, very well thought out process, very effective with members from many different departments. The teams from different departments get together and it is a team in excess of eight people contributing to this. So we have the discovery in the computer, sometimes by cloning, we determine the tissue distribution, we do full length cloning. These actually usually express at low levels so full length cloning is actually a challenge and then these receptors can'st really be expressed in bacterial cells even though there are some exceptions but you have to express them in a million cells and make stable lines and receptor will be on the surface. And once you have this what you need to do is for the receptors in the eye, you know, they will interact with light but these new receptors, what do they interact with? Do they interact with seratonnan? If they interact with seratonnan are they going to behave with the non-seraton receptors? I mean are they involved in migraine or in depression? So you need to figure all that out but the first thing to do is to figure out what ligand is interacting with your new receptor or your two hundred new receptors. So we have a very effective process where any non-ligand for 7 TM receptors or pudative ligand or suspected ligand. We created a bank, so we have a battery of 96 well plates turning now into 384 well plates that are ready to screen against all of these receptors as we get them available and also there are a lot of natural pet ties that interact with these receptors and we are making extracts and trying to identify new pet ties.

So once you have this, you have a ligand, you can set up high throughput screening. Sometimes you are not going to find a natural ligand and what we do is then we try, we set up the screen so that we can identify surrogate ligands from compound banks. Once you have this you can obviously progress to some evaluation and hopefully a drug discovery process.

I will show you a couple of examples of success stories. I have to say that along these two hundred or so we have matched about I think it is twenty-five or twenty-six, so about 10% have been matched with a ligand so it can show you that even though the process is very effective it actually is not totally optimized yet, it is a very difficult process and we try to improve it all the time. So I mentioned that we have matched a number of receptors and I am going to talk about two of them today, the Urotensin receptor and the melanin concentrating hormone receptor.

One is a receptor, the name is not really important. We identified a rat receptor in one of the public databases, a little piece of it and we said, Well whenever we see a new

receptor that we don'st have we go get the human, the human was not known. So we isolated the human based on some pieces of genomic information as well of very active fallings cloning team and I will talk to you about that later and we established a stable line that was expressing the receptor on its surface. I want to point out that the gene actually is turned on in the heart and also in the pancreas and that is helping us now trying to understand the possible disease indications for this receptor. What was most important is remember I told you about this bank of ligands that we have and we ran across all novel receptors that we identify and that bank contains a peptide that is actually isolated from fish that was suspected to be a ligand for a 7TN receptor but it had not been identified. So what we did is, we had the cell line, we had the bank, we ran these things matched, they found each other in the screen and we have now shown that there is a human counterpart to this peptide, the peptide is called uratensin and is a function in fish but the fish peptide as well as the human counterpart is actually a very potent vasoconstrictor. For those of you who have heard about vasoconstriction, ten years ago the important one was ET endrophilan. This peptide is actually ten times more potent, it is the most vasoconstrictor identified today. What we are trying to do now is understand, obviously everybody thinks about hypertension when you think about vasoconstrictor, what we are trying to do now is really identify what disease indications are the most appropriate, especially if you know that the expression in pancreas is very intriguing and there may be some other role in the activity of the pancreas.

Another one, again, don'st think we just work on fish, but it just so happened that this particular peptide had been reported in the literature both from fish and from an alien sources. For years people had been unable, for ten years they tried to identify the receptor for the melanin concentrating hormone peptide and this peptide it actually.a lot of work had been done but with other receptor you can'st do a lot of work and there were no tissues or cells responding to MCH. So what we did is we again took all of our receptors, ran, this is one of the peptides that is in the bank and one of the receptors that is called SLC1 showed a beautiful response to this particular peptide. We have done a lot of work to confirm a lot of published information on this particular peptide. It is indeed through in situ Hybridization located specifically in the hypothalamus, likely to have a role in feeding. So, again as I mentioned this was a discovery from over ten years ago but could not be exploited since the people didn'st have the target. So this is what we are looking at now in the context of feeding disorders.

So one of the things that for us is very key, early on if you remember the big scheme that we have developed to study these receptors, one of the early steps is to define the tissue distribution so we can do this in a number of ways. One method utilizes famous PCR technology and it is called the Realtime PCR Quantitative PCR, we also call it PACman, that is the name of the machine and you can see this particular novel orphan receptor, and orphan receptor doesn'st have its ligand, once they are paired, you know they are fine, they are no longer orphans. So you can see that this particular one is expressed, is turned on in the brain, this other one here is in microphages and the last one here across different things so, you know, knowing that it is in the brain, you immediately go and talk to biologists from the neural science department. When it is in microphages you talk to folks from immunology and so on and so forth. So this is not the answer to everything but it is a critical step to validating a target and obviously most of you have heard about gene chips, DNA micro-rays, gene micro-rays and what you can do here is on a small surface, a typical microscope blast slide you can put down ten thousand different genes and ask: Show me which ones are turned on in the brain?

Which ones are turned on in microphages? So we have included all of our 7TN receptors in the DNA micro-rays that we have developed in house. One of the things I want to show you here is the power of micro-rays, here insulin was we discovered as the RNA level when we take pancreatic eyelets that are not treated or treated with glucose, here's you know, if insulin had not been discovered we would have discovered using micro-ray technology.

Obviously this is looking atif you take a gene when it is turned on the first step is to make RNA, RNA is what is analyzed by micro-rays, this next step is to make protein and proteale mix is looking at protein. So ultimately what makes sense for the functioning and the structure of a body is to look at protein. The technology for looking at the RNA is a little bit more advanced and more sensitive at this time but you will hear more about proteale mix from another speaker later today.

So one of the things that we are doing is something that we call the Global Human Anatomy Project where we ideally will have every single human gene on a.maybe not on one slide because we can fit ten thousand but maybe on four or five slides and then probe to see. The ones that are turned on in the brain are shown in red, the ones turned on in the heart are in red here so you can see the differences. The brain is well know to have a very large number of genes turned on in its own complement.

Something that is very important is to pay attention to quality because if you do this wrong, actually these slides, I can show you very nice slides that were coming from complete garbage data. So that is something that I have worked on very hard internally and indeed with use of existing technologies to make sure that there is great quality because just a little bit of garbage up front, something that is not optimizing the technology in the gene selection or in the interpretation data leads to a huge amount of bad information and then it is going to be totally misleading. So that is something that is very critical in all these high profile technologies is to ensure that there is quality all along the way.

Something that I just want to spend a few minutes on is the tremendous promise that is also part of genomics of using model systems that are easy to manipulate compared to humans and obviously you all heard about yeast, it's the baker's yeast, and this is the worm C elegance and then obviously we have the fruit fly and the famous mouse and these have been extremely helpful. We have set them up, these technologies in house to various extents we are very strong in all at this time we are still kind of embryonic in our efforts with Rosoffula.

I'sm not going to walk through everything that can be done with yeast, with worm and with the mouse but this slide is really to tell you that the applications are tremendous. We have validated targets using just yeast because yeast has a lot of genes that are in common all the way to human. We are now in the process of utilizing the worm C elegance to also discover and validate targets but our efforts there is not as far on. In the mouse we have a very strong mouse genetics group re-focusing on over expressing genes or that so called transgenics or knocking out a gene function is called a knockout and I wanted to show you one example very briefly that is actually very telling where a new gene was identified that is involved in the regulation of energy expenditure.

Obviously your body metabolism, you will eat food, that is like taking in energy and then you will store some of it, most people don'st really want to store it in this particular form here, a three-letter word, an f's word but the expenditure is something, you know, alright, let's exercise, let's get all that stuff going, so that we don'st have accumulation in fat.'s

So there are a number of targets there obviously. One of the ones that we are looking at is a gene that is called UCP3, it is an uncoupling protein and it is expressed in the microcount where that is involved in the energy expenditure and what we did is we actually found that this gene is associated with skeletal muscle expression and what we decided to do was to make a lot of this in a mouse in the muscle, to mimic really where it is made in humans and what we saw, so these are mice that are overproducing the human UCP3 and it is highly conserved in the mouse but we used the human gene and what we found is that there was an increase in oxygen consumption, there was an elevated temperature but this was not a significant thing. The most important is that these mice could eat on what we called a palatable food, so the biologists say well it was good food that we gave them. So they eat like pigs but they don'st put any weight on and I think everybody in this room would love to do that. The problem with this particular target is that it is not really very palatable for the people to set up a screen and the chemist to attack it so we need to do much more work here in turning this into a viable target, probably by identifying something that interacts with or a pathway it is part of.

So you can see there are various approaches whether it is ligand fishing that we did with fish but believe me we are not just using fish, whether it is tissue distribution by the tackmand or the micro arrays or proteale mix or use of animal models, there are many, many different things out there that have to come together. For the Cat* story, all we needed to know was the sequence homology from the bioinformatics analysis, sequence homology to a protease like papain and to know that it was selectively produced by osteoclast. Here two pieces of the puzzle came together and said, This is likely to be a target, very likely to be a good target for osteoporosis and the compounds I think I forgot to mention, well it made it to pre-clinical, the cat* inhibitors made it to pre-clinical studies because they actually work in animal models of osteoporosis. So that was the final validation. So all these things, you can say, well, you know, we are really playing with all this and it is just a matter of putting all the right pieces together.

Something that is important is the way we got ourselves organized, organized the people who are a particular discipline, put them together so that you can have a focus on a co-activity whether it is a platform technology or biology or screening or chemistry. So you have everybody together, they can use, you know, standardize methods, they canbecause they are all together you can make a bigger investment of capital equipment, so and so forth so that it doesn'st have to be duplicated. You have a critical mass of people and constant peer reviews, so you have all the experts together. If you have a cloner, buried with a bunch of chemists, the chemists aren'st going to say, Well that guy is a genius and it could be the worst possible cloner on earth. So you can share experience, you minimize duplication, you win instead. Quality, as I said, very critical, you can assure this because you can impose very stringent standards, the cost saving, everything that is shared specially very expensive equipment and you can have tremendous levels of efficiency and productivity and creativity.

I just want to show you in cloning, this stands for full length genes so when we get genetic information many times they are just small bits and you need to isolate the whole gene. In the past I used to run this department, now it is somebody else, you can say, well, you are not running this effectively. I just imposed a change in the process and I don'st use the matrix to say, well we are a protease company, what is important is large numbers. Using the matrix to actually drive creativity, innovation, we have developed new approaches to isolate very rapidly very high quality full length human genes. Those are human genes and we have the process to isolate pieces of genes where, you know, we get a few hundred say in a month, because when it comes a piece of a gene is sufficient for example for micro-rays and we are also applying these new techniques to isolate genes all the way from the rat, the dog, the pig, bovine, ferret, even the tree, so we have a lot of species at our disposal.

Something that is obviously very important is a dialogue between the wet and the dry world and this is something that is not going to disappear and what is happening is that now there are curriculums in universities that are totally focused on bioinformatics. These people don'st have any understanding, they never did any wet work. In the past people who became bio-informaticists were biologists who had to learn it's they have the . do a background and now what you have is a lot of people just with biology background or just with bioinformatics background. It is amazing to put these people together and get them productive, it takes a lot of work. And obviously for compounds you also have informatics and we call it chem-informatics, trying to see what is in common with compounds that were leftoxic viabilities or things like that so we have a group focusing on this.

And then obviously in the past, you know, I grew up doing my PhD in Belgium and the big thing was my Bunsen burner and a toothpick, I mean really, you talk about stoneage and now this is the types of instrumentation to help us with quality, with throughput. These machines, they are going to work 24 hours a day, they are going to work all days in the year, they are not going to ask for a raise, they don'st need a bathroom, so they can have different buildings that are, you know, open up with umbilical cords going to the ceiling for power and information. So a tremendous change in the way we do things. So we are not static dinosaurs.

And the last point is genomics is equally contributing to the understanding of diversity, what is similar between people as well as different, not just the way they look but the way to respond to drugs, both in efficacy as well as in..usually this has a better effect in the US where people know the caste of characters. I need to be more trans-national, this is actually taken from Spy Magazine so I will stop here and we may have time for one question otherwise we will be late for the other speakers.

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